The CNS synthesizes and secretes several neuropeptides which attenuate the actions of morphine including CCK-8, Tyr-MIF, Phe-Leu-Phe-Gln-Pro- Gln-Arg-Phe-NH2 (NPFF), alpha-MSH and dynorphin(1-17). The anti-opioid model of tolerance and dependence postulates that administration of morphine produces increased secretion of anti-opioids, which attenuate the effects of morphine, and thereby maintain a homeostatic balance. A prediction of the anti-opioid model is that administration of an anti- opioid should attenuate the development of tolerance and dependence. A previous finding of this project is that administration of anti-NPFF IgG to dependent rats attenuates naloxone-induced withdrawal. Autoradiographic studies have recently shown that the density of the opioid mu receptor in the brain is under tonic inhibitory control by NPFF. Importantly, the mu receptors in the mesolimbic system are regulated by NPFF. Published studies indicate that NPFF antagonizes the reinforcing effects of morphine. A recent study showed that chronic i.c.v. administration of NPFF down-regulates mu opioid receptors in different areas of the brain than does chronic i.c.v. administration of morphine. Heroin addicts suffer from dysphoric mood states prior to and during their addiction, as well as during periods of abstinence. One hypothesis to explain this is increased levels of dynorphin, which, via activation of kappa opioid receptors, produces dysphoria. The significance of this project to drug abuse research is that the delineation of novel mechanisms involved in opioid tolerance and dependence will eventually lead to novel, and more specific treatments for addiction. The strong association of high risk behaviors related to the spread of HIV with opioid addiction makes the effort to develop new treatment medications highly related to the fight against AIDS.